A Serious New Hurdle For CRISPR (Gene Edit): Edited Cells Might Cause Cancer, Find Two Studies

[DamianTV]

https://science.slashdot.org/story/1...nd-two-studies

Editing cell genomes with CRISPR-Cas9 might increase the risk of developing cancer, two studies published Monday warn. From a report:

Editing cells' genomes with CRISPR-Cas9 might increase the risk that the altered cells, intended to treat disease, will trigger cancer, two studies published on Monday warn -- a potential game-changer for the companies developing CRISPR-based therapies. In the studies, published in Nature Medicine, scientists found that cells whose genomes are successfully edited by CRISPR-Cas9 have the potential to seed tumors inside a patient. That could make some CRISPR'd cells ticking time bombs, according to researchers from Sweden's Karolinska Institute and, separately, Novartis. CRISPR has already dodged two potentially fatal bullets -- a 2017 claim that it causes sky-high numbers of off-target effects was retracted in March, and a report of human immunity to Cas9 was largely shrugged off as solvable. But experts are taking the cancer-risk finding seriously.

Key Word there is "Might". I can entertain the idea that in certain circumstances, it would be possible, but probably not in all situations?

[Zippyjuan]

Link to the original article: https://www.statnews.com/2018/06/11/...-cause-cancer/

On the other hand, the Novartis paper has been available in preliminary form since last summer, and CRISPR experts “haven’t freaked out,” said Erik Sontheimer of the University of Massachusetts Medical School, whose CRISPR research centers on novel enzymes and off-target effects. “This is something that bears paying attention to, but I don’t think it’s a deal-breaker” for CRISPR therapies.

The Karolinska and Novartis groups tested CRISPR on different kinds of human cells — retinal cells and pluripotent stem cells, respectively. But they found essentially the same phenomenon. Standard CRISPR-Cas9 works by cutting both strands of the DNA double helix. That injury causes a cell to activate a biochemical first-aid kit orchestrated by a gene called p53, which either mends the DNA break or makes the cell self-destruct.

Whichever action p53 takes, the consequence is the same: CRISPR doesn’t work, either because the genome edit is stitched up or the cell is dead. (The Novartis team calculated that p53 reduces CRISPR efficiency in pluripotent stem cells seventeenfold.) That might explain something found over and over: CRISPR is woefully inefficient, with only a small minority of cells into which CRISPR is introduced, usually by a virus, actually having their genomes edited as intended.

“We found that cutting the genome with CRISPR-Cas9 induced the activation of … p53,” said Emma Haapaniemi, the lead author of the Karolinska study. That “makes editing much more difficult.”

The flip side of p53 repairing CRISPR edits, or killing cells that accept the edits, is that cells that survive with the edits do so precisely because they have a dysfunctional p53 and therefore lack this fix-it-or-kill-it mechanism.

Which raises an obvious question — if successfully CRISPR’d cells can seed cancers, why hasn’t this been seen before, and why haven’t the many CRISPR’d mice developed tumors?

Karolinska’s Haapaniemi said the effect shows up in large-scale experiments like hers and Novartis’ “but can be missed in small-scale studies where people only focus on editing one gene in one cell type.” In speaking to other scientists, she said, “it seems that other teams have noticed the effect of p53 on editing,” but have not highlighted it.

Jacob Corn of the University of California, Berkeley, said that although his lab has seen evidence of p53 activation in a few cases, they have “looked hard for growth effects after editing in [hematopoietic stem cells] and found nothing.” He has “no reason to doubt the pluripotent stem cell results” in the new research, he added.

As for why no one has reported CRISPR’d mice getting cancer, Haapaniemi said, “This is a good question.” One reason might be that “laboratory mice are killed early,” perhaps leaving too little time for them to develop cancer.

But Corn said he and others “have all been looking for the possibility of cancer. So far, no one has seen evidence of [it] based on p53 status or induced by editing.”